Phase I Study of Pazopanib in Patients with Advanced Solid Tumors and Hepatic Dysfunction: A National Cancer Institute Organ Dysfunction Working Group Study

Shibata, Stephen; Chung, Vincent; Synold, Timothy W.; Longmate, Jeffrey; Suttle, A. Benjamin; Ottesen, Lone H.; Lenz, Heinz‐Josef; Kummar, Shivaani; Harvey, R. Donald; Hamilton, Anne; O’Neil, Bert H.; Sarantopoulos, John; LoRusso, Patricia; Rudek, Michelle A.; Dowlati, Afshin; Mulkerin, Daniel; Belani, Chandra P.; Gandhi, Leena; Lau, Sien-Ting; Ivy, S. Percy; Newman, Edward M.

doi:10.1158/1078-0432.ccr-12-3214

Cited by 62 publications

(41 citation statements)

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“…The upper limits of normal for these tests were made independent of local laboratory definitions. Liver toxicity was assessed multiple ways given the complexities that an individual test is not sufficiently robust: (1) Alterations in liver tests were assessed utilizing the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 to grade liver test results, (2) The NCI Organ Dysfunction Working Group (ODWG) definitions for hepatic dysfunction were used to define baseline and peak categorizations (Table 1)(15), (3) A modified version of the US FDA R ratio [(ALT value/ALT ULN)/(ALK value/ALK ULN)] was used to classify the pattern of liver test abnormalities (Table 1)(16, 17), and (4) Hy’s Law was also utilized as previously described (Table 1)(18). For the definition of peak we used the most severe of whichever test.…”

Section: Subjects/methodsmentioning

confidence: 99%

“…Therefore, the Cancer Therapy Evaluation Program (CTEP) at the National Cancer Institute (NCI) prioritized study of these special patient populations with hepatic dysfunction in phase 1 clinical trials (HDCT) to determine safe administration parameters of antineoplastic agents for subjects with varying degrees of liver dysfunction. HDCT sponsored by CTEP and others have provided clinically useful information on the optimal dosing of anti-neoplastic agents in subjects with different degrees of liver test abnormalities that have provided administration guidance in the labels for patients with abnormal organ function (5–15). …”

Section: Introductionmentioning

confidence: 99%

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The Effect of Hepatic Impairment on Outcomes in Phase I Clinical Trials in Cancer Subjects

Mansfield

Rudek

Vulih³

et al. 2016

Clinical Cancer Research

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Purpose The NCI Cancer Therapy Evaluation Program sponsors hepatic dysfunction phase 1 clinical trials (HDCT) and phase 1 clinical trials (P1CT) to determine safe doses and schedules of antineoplastic therapeutics. We sought to compare clinical outcomes between these trial types while stratifying by hepatotoxic agents. Experimental design Individual subject data were extracted from the records of 51 NCI-sponsored HDCT and P1CT. The NCI’s Organ Dysfunction Working Group’s hepatic impairment categorization and two drug-induced liver injury (DILI) scales (FDA R ratio and Hy’s law) were used to classify subjects. The number of cycles administered and treatment discontinuation reason were also evaluated and compared between groups. Results There were 513 and 1328 subjects treated on HDCT (n=9) and P1CT (n=42), respectively. There were differing patterns of DILI with significant worsening of total bilirubin in subjects on HDCT, and worsening of ALT in subjects on P1CT. Cholestatic peak patterns of liver impairment (predominant increases in alkaline phosphatase rather than transaminases) were more frequent in HDCT. Criteria for Hy’s Law were met by 11 subjects on P1CT but not by any subjects on HDCT. Disease progression was the most common reason for treatment discontinuation, followed by adverse events at similar frequencies in both HDCT and P1CT. Conclusions The differential effects on hepatotoxicity suggest that underlying hepatic function may affect susceptibility to and patterns of DILI. The incorporation of additional measures of hepatic function may help identify those at highest risk of hepatotoxicity in future trials since baseline liver tests did not.

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Section: Subjects/methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The Effect of Hepatic Impairment on Outcomes in Phase I Clinical Trials in Cancer Subjects

Mansfield

Rudek

Vulih³

et al. 2016

Clinical Cancer Research

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“…Based on Younis's work comparing the sensitivity of liver function classification systems for exposure changes, the NCI scale appears to be the most precise for indicating exposure changes in hepatically impaired cancer patients [13] . Multiple studies have used the NCI scale to classify cancer patients according to the degree of hepatic impairment and to inform dosing recommendations in these subpopulations [14][15][16][17] . Recently, the FDA suggested using the NCI scale as an alternative to the Child-Pugh scale for hepatic impairment classification in oncology trials [18] .…”

Section: Classification Of Hepatic Impairmentmentioning

confidence: 99%

A Review of Regulatory Guidance for Conducting Hepatic Impairment Studies: A Case Study in Oncology

Lin¹,

D’Cunha²

2018

JOCR

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Running Title: Review of regulatory guidance for hepatic impairment studies ABSTRACTThe liver is a vital organ that plays a central role in the metabolism and elimination of drug molecules. Impairment of this vital organ can lead to increased accumulation of parent drug or active metabolites, affecting systemic drug disposition, clinical efficacy, safety and tolerability. Hepatic disease in cancer patients is generally associated with the metastatic spread of the primary tumor to or near the liver, or by toxicities associated with treatment using chemotherapeutic agents. Over the last decade, the understanding of cancer has changed the field of drug development and has resulted in novel, oral targeted therapies that interfere with dysregulated pathways in cancer. Many of these orally administered agents are dependent on the liver for drug metabolism and so understanding hepatic impairment in cancer is imperative to achieve appropriate dose adjustments and to avoid toxicity. This mini-review will focus on how published guidance from the US Food & Drug Administration (FDA) and European Medicines Agency (EMEA) on hepatic impairment studies can be tailored to guide study design and subsequent dosage modification in cancer patients with varying degrees of hepatic dysfunction.

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“…64,65 Therefore, correlation of C trough with response could be similar to that of AUC, and TDM could be based on the C trough target.…”

Section: Pharmacokinetic Properties Of Specific Oral Agents That Are mentioning

confidence: 99%

Pharmacokinetic‐Guided Dosing of New Oral Cancer Agents

Lucas

Martin

2017

The Journal of Clinical Pharma

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Generally, licensed drug-dosing recommendations for chemotherapy are based on results from clinical trials in which subjects are usually of relatively normal body size, middle-aged, and are relatively racially homogeneous, with minimal comorbidity and specific tumor characteristics. Very few nontrial patients meet these characteristics, resulting in clinical practice having to extrapolate dosing recommendations to the specific patient. There is insufficient research on the impact of obesity-associated physiological changes prevalent in patients with common cancers on standard pharmacokinetic and pharmacodynamic parameters. Yet quantifying the influence of obesity on the pharmacology of chemotherapy is vital, as dosing inappropriate for body composition (ie, flat dosing or mg/kg based on total body weight) may increase the risk of adverse events and reduce clinical effectiveness. Unfortunately, there are few cancer guidelines to aid clinicians in selecting the optimal dose in the obese-even recent guidelines are based predominantly on clinical opinion/current practice in treating obese patients, rather than evidence. Data in many other vulnerable groups, for example, those with significant comorbidity and older patients, are also scarce. Because of the known limitations of body surface area-guided dosing, therapeutic drug monitoring or pharmacokinetic-guided dosing, which predicts an individual's exposure, has increasingly been shown to be a powerful tool in cancer therapy. Used appropriately, it can adjust for differences in pharmacokinetic parameters not considered when body size-based dosing or "one dose fits all" is used. This review will focus predominantly on the rationale for pharmacokinetic-guided dosing of the newer oral molecularly targeted antineoplastics in people whose drug exposure is not predicted by their physiology or body composition.

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Phase I Study of Pazopanib in Patients with Advanced Solid Tumors and Hepatic Dysfunction: A National Cancer Institute Organ Dysfunction Working Group Study

Cited by 62 publications

References 10 publications

The Effect of Hepatic Impairment on Outcomes in Phase I Clinical Trials in Cancer Subjects

The Effect of Hepatic Impairment on Outcomes in Phase I Clinical Trials in Cancer Subjects

A Review of Regulatory Guidance for Conducting Hepatic Impairment Studies: A Case Study in Oncology

Pharmacokinetic‐Guided Dosing of New Oral Cancer Agents

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